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Table of Contents 
REVIEW ARTICLE
Year : 2021  |  Volume : 66  |  Issue : 4  |  Page : 386-392
Extracorporeal Therapy in Dermatology


Department of Dermatology, IPGME&R, Kolkata, West Bengal, India

Date of Web Publication17-Sep-2021

Correspondence Address:
Tirthankar Gayen
Department of Dermatology, IPGM&R, Kolkata, West Bengal; Madhabpur, Diamond Harbour, South 24 Parganas, West Bengal – 743331
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.IJD_897_20

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   Abstract 


Extracorporeal therapy is a treatment modality where human blood undergoes favorable technical modifications and is reintroduced into the same patient. Since the last four decades this technique has been deployed in the management of difficult and refractory disorders in dermatology. Over a period of time newer techniques like immunoadsorption has emerged and opened new vistas in management of morbid dermatoses. In extracorporeal photopheresis a patient's leukocytes are separated and treated outside with Ultra Violet A in presence of 8-methoxypsoralen. Double filtration plasmapheresis and Immunoadsorption are techniques to remove offending immune complexes. They are safe and reduce the need of toxic medications that are conventionally used in recalcitrant skin diseases. In recent years immunoadsorption is emerging as first-line therapy in condition like immunobullous diseases. High cost is one of the important factors limiting their wider use in developing countries like India. Our review discusses different extracorporeal therapies, their applications, recommendations and guidelines based on various clinical trials.


Keywords: Extracorporeal photopheresis, extracorporeal therapy, immunoadsorption, plasmapheresis


How to cite this article:
Sen S, Rudra O, Gayen T. Extracorporeal Therapy in Dermatology. Indian J Dermatol 2021;66:386-92

How to cite this URL:
Sen S, Rudra O, Gayen T. Extracorporeal Therapy in Dermatology. Indian J Dermatol [serial online] 2021 [cited 2021 Dec 3];66:386-92. Available from: https://www.e-ijd.org/text.asp?2021/66/4/386/326147





   Introduction Top


Extracorporeal therapy is emerging as an effective modality to treat a wide range of cutaneous as well as systemic disorders with cutaneous manifestations. The term "extracorporeal" denotes interventions taken outside the human body.[1] In this therapy human blood is drawn which undergoes specific treatment before reinfusion into human body. In accordance with different techniques adopted there are several types of extracorporeal therapies such as, extracorporeal photopheresis (ECP), immune-adsorbtion (IA), therapeutic plasma exchange (TPE), double filtration plasmapheresis, lipoprotein apheresis (LA), hemodialysis and different cytapheresis. It has many advantages over conventional therapy, like lowering effective drug dosage, minimum systemic adverse effects and more specific approach targeting offending factors.[1]

Extracorporeal photopheresis (ECP) was first reported by Edelson et al. in 1987[2] and was approved by the U.S. Food and Drug Administration for the treatment of advanced cutaneous T-cell lymphoma (CTCL) in 1988.[3]


   Different Types of Extracorporeal Therapy Top


Extracorporeal photopheresis

Extracorporeal photopheresis (ECP) which is synonymous with extracorporeal photochemotherapy, is a type of immunotherapy primarily targeting T-cell population of immune system. In this technique patient's blood is drawn, leukocytes (buffy coat) are separated and treated with Ultraviolet A (UVA) light in presence of a photosensitizer, 8-methoxypsoralen (8-MOP), followed by reinfusion. This eliminates gastrointestinal and ocular side effects of 8-MOP and also reduces its dosage as in conventional phototherapy.

Two techniques are followed in ECP. In "On-line" or "Open system" in which all the steps (leukapheresis, photoactivation, and reinfusion) are performed sequentially in a single instrument (Therakos UVAR XTS or Therakos CELLEX) having US FDA approval.[4] In "Off-line" or "Closed system" as proposed by Andreu et al. in 1994, separate instruments (COBE Spectra/Terumo BCT and UVA irradiator) are used for different steps in ECP with the advantages of dealing with low extracorporeal volume, higher cellular harvest with minimum use of anticoagulant making it perfectly suitable for pediatric patients.[4]

Indications

Edelson et al. were one of the first to introduce ECP to treat cutaneous T-cell lymphoma (CTCL).[2] Later in 1988, the US Food and Drug Administration approved the use of ECP as standard therapy for the treatment of patients with advanced refractory CTCL. Afterward, it has been applied in several autoimmune T-cell-mediated diseases.[5] Lists of dermatological conditions where ECP can be used has been laid down by the American Society for Apheresis guidelines in 2016 [Table 1].[6]
Table 1: Lists of dermatological conditions where ECP can be used, laid down by American Society for Apheresis guidelines in 2016[6]

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Cutaneous T-cell lymphoma (CTCL)

ECP has been established as a first-line treatment in CTCL patients with blood involvement (stage IVA1 or IVA2) and erythrodermic stage IIIA or IIIB. The rationale behind this modality is that psoralen and UVA induce apoptosis selectively to malignant leukocytes. This is followed by phagocytosis by antigen-presenting cells (APCs) and subsequently stimulation to monocyte differentiation of myeloid dendritic cells with Th1 phenotype that launches cytotoxic effects against malignant lymphocytes.[7] The very initial study by Edelson and colleagues in 1987 showed ECP to be a promising therapy. Among 37 patients, 27 (73%) responded to treatment, with an average 64% decrease in skin involvement and nine of these patients had a complete response.[2] Later data has been re-analyzed using modern criteria and found to depict overall response rate of 74%, achieving ≥50% partial skin response that included 41% achieving ≥90% improvement.[8] Talpur et al. found 42% response rate in the early stages of mycosis fungoides in their multicentric clinical trial.[9] Usual regime is two consecutive days of therapy at an interval of two weeks for three months and subsequently according to response. Many studies observed better response along with adjuvant therapy with interferon-alpha or bexarotene.[10],[11]

Graft versus host disease (GVHD)

ECP is used in both acute and chronic GVHD especially in steroid-refractory cases as second-line therapy. 8-methoxypsoralen and UVA treated lymphocytes undergo apoptosis and show immune-modulatory responses in the form of increased dendritic cell differentiation, downregulation of autoreactive B cells, alterations in T helper cells and lymphocyte homing antigen display, switch from pro-inflammatory to anti-inflammatory cytokine generation and regulatory T-cell production.[10] Currently consecutive two days of therapy at an interval of two weeks for 8 months is recommended. A retrospective multicentric study found 80% response in GVHD with ECP.[12] A very recently published article mentioned ECP as an initial prophylactic treatment indicating its beneficial effect in preventing GVHD.[13]

Scleroderma

Role of ECP in different studies showed varying responses. A randomized controlled trial (RCT) by Knobler et al. showed significant improvement in skin scores and mean joint involvement in 6–12 months period.[14] Another multicenter RCT showed a statistically significant improvement in skin and joint parameters at 6 months among 68% of ECP treated patients compared to 32% patients on D-penicillamine.[15] But Enomoto et al. did not find any statistically significant response in their RCT with cross-over study design.[16]

Atopic dermatitis

Several controlled studies were conducted to assess the efficacy of ECP in atopic dermatitis. Many of them showed good response in skin improvement mainly in refractory cases.[17] Kopplhus et al. found equipotency of ECP to cyclosporine in severe atopic dermatitis.[18]

Psoriasis

The pathophysiology of psoriasis indicates that ECP might have positive role in its management. There are very few studies available which show variable response. Molochkov VA et al. showed a high efficiency in patients with psoriasis and psoriasis associated with psoriasis arthritis in their comparative study.[19] Vonderheid EC and colleagues found that extracorporeal photopheresis has incomplete suppressive effect on psoriasis vulgaris as monotherapy. The outcome may be enhanced by concomitant use of low doses of methotrexate.[20]

Hemodialysis

Hemodialysis is a diffusion-based technique where small and some middle-sized molecules of blood cross a semipermeable membrane from higher to lower concentration. Hemodialysis can be intermittent or continuous venovenous. Intermittent hemodialysisis is more commonly used in removal of toxins with low molecular weight, low protein-binding, and low volume of distribution and in overdosage of various drugs and chemicals.[21] There are other procedures, like hemofiltration (convection-based procedures where middle molecular substances cross semipermeable membrane according to a pressure gradient); hemodiafiltration (combined diffusion-convection-based); hemoperfusion (adsorption process where component of blood bind to surface of a column).[21] These procedures are used extensively for blood purification in different pathological disorders.

Plasmapheresis

Plasmapheresis is a treatment modality based on the concept of purification of blood to cure a disease. It is basically removal of plasma or the pathogenic parts from other components of blood and reinfusion with replacement fluids. The terminology was first used by Abel et al.[22] in 1914 but accelerated clinical use started after introduction of continuous or intermittent automated centrifuge machines. Different techniques have been developed for this purpose. Centrifugal separation is performed, where plasma is removed based on the sedimentation property of blood components using high-speed central flow centrifuge.[23] Sometimes different semi-permeable membranes are used to separate in plasmapheresis, based on molecular size.[24] Recently on-line plasmapheresis technique is being used in which the separated and treated plasma is re-infused with cellular components minimizing the need for replacement of fluids.[25]

Therapeutic plasma exchange (TPE) is referred to the technique where whole plasma containing pathogenic materials is discarded and completely replaced with suitable fluid with cellular components.[25]

Varieties of replacement fluid used during plasmapheresis include albumin, electrolyte solutions, fresh frozen plasma, hydroxyethyl starch and purified protein products like clotting factors or antithrombin III. Albumin is the most common replacement product because of its easy availability and low side-effect profile. Replacement product is chosen based on the underlying disease and the risks and benefits ratio of each replacement product.[26]

Plasmapheresis can be used in different dermatological conditions like systemic lupus erythematosus, toxic epidermal necrolysis, pemphigus (including pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus), vasculitis, dermatomyositis, drug-induced erythroderma or drug toxicity, systemic sclerosis, scleromyxoedema, pyoderma gangrenosum, psoriasis, atopic dermatitis, hepatobiliary pruritus, Refsum's disease.[27]

Applications of plasmapheresis

Systemic lupus erythematosus (SLE)

Only SLE with severe complications can be treated with therapeutic plasma exchange as second line therapy with an intention to remove the pathogenic autoantibodies or immune complexes. But no significant controlled trials are available in favor of this both clinically or serologically.[7],[28]

Familial hypercholesterolemia

Lipoprotein apheresis (LA) can be applied in case of type IIa familial hypercholesterolemia (homozygotes). Available evidences suggest it can reduce the concentration of cholesterol and low-density lipoproteins resulting in resolution of the skin xanthomas.[29] Thompson et al. had documented promising results among 20 patients who were treated by plasma exchange either at weekly or monthly interval for a period of 5 years.[30]

Refsum's disease

It is an autosomal recessive phytanic acid storage disease due to deficiency or defect in enzyme phytanoyl-CoA-hydrolase involving multiple system.[31] TPE and LA along with dietary modification showed significant recovery from ichthyotic skin rash, neuropathy and cardiac arrhythmias.[31],[32]

Vasculitis

Plasmapheresis is recommended in ANCA associated vasculitis with severe complications. TPE has also been used to treat severe gastrointestinal or skin manifestations and cerebritis in Henoch-Schonlein purpura.[7] TPE can be used in case of Hepatitis B Virus-associated polyarteritis nodosa. Several case studies suggested its effectiveness along with corticosteroids and anti-viral therapy.[33] No benefit had been documented in case of idiopathic PAN, even in many randomized control trials (RCT).[34]

Atopic dermatitis

Since last two decades many controlled studies in >100 patients have been published with about 70% of patients having a favorable response to plasmapheresis, requiring at least 6 cycles for a response.[35] IgE specific immune-adsorption has also been used in recalcitrant atopic dermatitis. Though serum IgE showed a short term control but skin bound antibodies were reduced for a long time, improving skin condition.[36]

Psoriasis

The rationale behind the use of adsorptive cytapheresis or TPE in psoriasis was to remove the offending cytokines and related factors. Studies failed to show definite benefits because in most of them TPE or cytapheresis was combined with other standard therapy of psoriasis like methotrexate or cyclosporine.[37]

Scleroderma

TPE is used in this condition in an intention to remove the pathologic humoral factors. An RCT with 15 patients showed some serological improvement but no difference in clinical outcome.[38] One clinical study with 14 patients showed improvement but the study used concomitant prednisolone and cyclophosphamide.[39]

Toxic epidermal necrolysis (TEN)

No RCTs or Clinical trials are available in this disorder. Few studies showed some benefit of TPE but no definite conclusion can be drawn due to varied presentation, severity of disease and concurrent use of other medications.[7]

Drug overdose/toxicity or poisoning

TPE has been used in various drug overdose and poisoning cases.[40]

Immunobullous diseases

The rationale behind TPE in pemphigus is to eliminate offending circulating autoantibodies. Guillaume et al. did not find any significant steroid sparing benefits in their RCT with 40 cases of pemphigus, though few monocentric controlled studies and reports claimed to achieve some benefits.[41] Mazzi et al. found almost 70% reduction in steroid doses among all patients with pemphigus and bullous pemphigoid in their controlled trial.[42]

Common adverse effects of plasmapheresis are worsening of controlled seizure due to decrease in the serum level of anticonvulsants, hemorrhagic episodes, deranged osmoregulation, and infusion related hypersensitivity, phlebitis, hypocalcemia and increased chance of infections.[25],[42]


   Double Filtration Plasmapheresis Top


Double filtration plasmapheresis (DFPP) is a special type of plasmapheresis where two filters with different sized pores are used which selectively remove the immunoglobulin fraction from the serum minimizing the volume of substitution fluid required. In this procedure usually 0.5–1.0 L of an 8% albumin solution is used as replacement fluid compared to 2.5–5.0 L of fresh plasma used in regular plasma exchange.[43] DFPP can be used in immunobullous diseases. Hatano et al. suggested that regulation of expression of different cytokines and chemokines might play a major role in case of bullous pemphigoid.[44] Higashihara et al. found significant reduction in autoantibody titer and disease area severity index after successful treatment with DFPP among five steroid unresponsive pemphigus patients.[45] Similar observation was documented by Yan et al. where they retrospectively analysed 17 high dose steroid unresponsive pemphigus patients who received DFPP treatment between January 2010 and January 2020.[46]

In one study Jin-Young Kim and colleagues showed significant clinical improvement among nine recalcitrant atopic dermatitis patients following DFPP.[47]

Bacteremia is one of the most common adverse effects of DFPP.[48]


   Immunoadsorption Top


Immunoadsorption (IA) also termed as immunoapheresis is an effective and advanced method for the treatment of autoimmune disorders. The main advantage of this method is that specific antibodies and immune complexes can be removed from the circulation. As it does not remove other plasma components like fibrinogen, and coagulation cascade proteins, so chances of adverse effects are also less. IA can be used effectively in different immunobullous disorders, like in pemphigus (IgG autoantibodies against desmoglein 1 and 3); in paraneoplastic pemphigus (antibody against plakin family proteins); in pemphigoid group of disorders (antibody against BP180 and BP230, laminin 332 and α6β4 integrin). Studies showed different IA protocols for reducing circulating autoantibodies.[49] In all protocols, IA was used in combination with either systemic corticosteroids or with immunosuppressive drug (like azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil or rituximab). Meyersburg et al. proposed one IA cycle on three consecutive days followed by additional cycles after 3 weeks and then in 4-week intervals till 90% clearance of the lesions.[49]

Eming et al. evaluated efficacy and safety of peptide based adsorber system among severe and therapy resistant pemphigus patients in their study and found one IA cycle reduced anti-Dsg1 and anti-Dsg3 autoantibodies by an average of 50–70% as determined by ELISA.[50]

IA has now been used in the treatment of recalcitrant atopic dermatitis. Recent studies showed significant favorable alteration in IgE level following IA therapy.[51]

IA can also be used successfully in the treatment of resistant connective tissue diseases, such as systemic lupus erythematous, systemic sclerosis, mixed connective tissue disease and in dermatomyositis as autoantibodies play a significant role in the pathogenesis of these disorders.[52]


   Cytapheresis Top


Cytapheresis is an emerging therapeutic modality where the selective removal of RBCs, WBCs, or platelets is performed and can be accomplished by using identical centrifuge-based equipment. Tominaga and colleagues found cytapheresis helpful in the majority of patients with pyoderma gangrenosum (PG) refractory to medical treatment associated with inflammatory bowel diseases.[53]

Category and grade recommendation for therapeutic apheresis are mentioned in [Table 2].[7]
Table 2: Category and grade recommendation for therapeutic apheresis as per the Journal of Clinical Apheresis (JCA) Special Issue Writing Committee of The American Society for Apheresis (ASFA) in 2019[7]

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   Conclusion Top


Though several studies documented different extracorporeal therapies improved a number of dermatological disorders, its true efficacy remained unproven in most instances. In spite of a number of side effects, these are still relatively safe compared with other modalities of treatment. ECTs however are costly and many a time additional immunosuppressive agents are required for better efficacy. Limited facilities exist in a developing country like India. So, extracorporeal therapies are kept in reserve only to be used in refractory situations. Recently newer sophisticated techniques, like immunoadsorption, double filtration plasmapheresis are emerging specially to treat life-threatening or "difficult to treat" dermatological diseases as first-line therapies leading to improvement in quality of life and decreasing mortality with minimum side effects. Future researches are necessary for optimization of therapy, standardization of existing protocol and availability of different bio-markers to monitor the therapy for better outcome.

Grading recommendation: Grade 1A to 1C = Strong recommendation with high, moderate and low quality evidence respectively, 2A to 2C = Weak recommendation with high, moderate and low quality evidence respectively.

Acknowledgement

The authors appreciate the critical review of Prof. Dwijendra Nath Gangopadhyay in the preparation of this manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

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    Abstract
   Introduction
    Different Types ...
    Double Filtratio...
   Immunoadsorption
   Cytapheresis
   Conclusion
    References
    Article Tables

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